There are currently no effective treatments for acute neural injuries (such as stroke and spinal cord injury) and chronic neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amytrophical lateral sclerosis, retinal degeneration, etc.). Drugs that can protect neurons and/or promote neuroregeneration are urgently needed to treat these devastating injuries or diseases, as well as promote memory formation.
Neurotrophic growth factors (including nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 and -4/5, ciliary neurotrophic factor, glial cell-derived neurotrophic factor, and fibroblast growth factor) have emerged in the past decade as promising drug candidates for treating acute and chronic neurodegenerative diseases. These protein neurotrophic growth factors play an essential role in the maintenance of neuronal populations from development through adulthood. However, clinical studies with these protein-based neurotrophic factors have proved to be disappointing due to their poor pharmacokinetic behavior, low bioavailability, inability to penetrate the brain, and pleiotropic effects. Therefore, much effort has been invested in the search for non-peptidyl small neurotrophic molecules.
Additional targets of interest include CaM Kinase II, which is involved in memory formation.
Small neurotrophic molecules have the potential to be administered orally and to successfully traverse the blood/brain barrier. Numerous companies around the world have invested heavily in this area for many years and screened tens of thousands of compounds. Unfortunately, however, no compounds have been identified thus far which are promising enough to go to clinical trials (for reviews of this field, see Thoenen and Sendtner, Nat. Neurosci. Supplement 5, 1046-1050 (2002); Saragovi and Gehring, Trends Pharmacol. Sci. 21, 93-98 (2000); Xie and Longo, Prog. Brain Res. 128, 333-347 (2000)).
An abnormal rate of apoptosis may be responsible for at least some of the neuronal cell death in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (Thompson, Science 267, 1456-1462 (1995)). Inhibitors of the apoptosis pathway therefore can be used to promote neuronal survival. Peptide-based inhibitors of caspases, key enzymes in the apoptosis pathway, will suffer from the same drawback as neurotrophins in terms of their ability to cross the blood-brain barrier. Small molecule inhibitors of the apoptosis pathway are still in the early exploratory stage (for review, see Huang, Chem. & Biol. 9, 1059-1072 (2002)).
Accordingly, there is still a need in the art for compounds that can protect neurons and/or promote neuroregeneration and/or promote memory formation. Such compounds will be useful for treatment of a variety of neural disorders and conditions.